Background The pharmacokinetic (PK) properties of extended half-life (EHL) factor VIII (FVIII) concentrates differ, leading to variation in the optimal dosing regimen for the individual patient. The aim of this study was to establish these PK differences for various EHL FVIII concentrates by in silico simulations. Methods FVIII level over time profiles of rFVIII-SC, BAY 81–8973, rFVIII-Fc, BAX 855, BAY 94–9027, and standard half-life (SHL) rFVIII concentrates were simulated for 1,000 severe hemophilia A patients during steady-state dosing of 40 IU/kg every 72 hours or dosing as advised in the summary of product characteristics (SmPC). Results Although the elimination half-life values were comparable for rFVIII-FC, BAX 855, and BAY 94–9027, a higher area under the curve (AUC; 2,779 IU/h/dL) for BAY 94–9027 was obtained. During steady-state dosing of 40 IU/kg every 72 hours, 58.5% (rFVIII-SC), 69.3% (BAY 81–8972), 89.0% (rFVIII-Fc), 83.9% (BAX 855), and 93.7% (BAY 94–9027) of the patients maintained a trough level of 1 IU/dL, compared with 56.0% for SHL rFVIII. Following dosing schemes described in the SmPC, between 51.0 and 65.4% or 23.2 and 31.1% of the patients maintained a target trough level of 1 IU/dL or 3 IU/dL, respectively. Conclusion BAY 94–9027 showed the largest increase of AUC and best target attainment compared with SHL rFVIII, followed closely by BAX 855 and rFVIII-Fc. BAY 81–8973 and rFVIII-SC showed smaller PK improvements. Although our analyses increase insight into the PK of these FVIII concentrates, more studies evaluating the relation between factor levels and bleeding risk are needed.

Purpose Hemophilia B is a bleeding disorder, caused by a factor IX (FIX) deficiency. Recently, FIX concentrates with extended half-life (EHL) have become available. Prophylactic dosing of EHL-FIX concentrates can be optimized by assessment of individual pharmacokinetic (PK) parameters. To determine these parameters, limited sampling strategies (LSSs) may be applied. The study aims to establish adequate LSSs for estimating individual PK parameters of EHL-FIX concentrates using in silico evaluation. Methods Monte Carlo simulations were performed to obtain FIX activity versus time profiles using published population PK models for N9-GP (Refixia), rFIXFc (Alprolix), and rIX-FP (Idelvion). Fourteen LSSs, containing three or four samples taken within 8 days after administration, were formulated. Bayesian analysis was applied to obtain estimates for clearance (CL), half-life (t1/2), time to 1% (Time1%), and calculated weekly dose (Dose1%). Bias and precision of these estimates were assessed to determine which LSS was adequate. Results For all PK parameters of N9-GP, rFIXFc and rIX-FP bias was generally acceptable (range: −5% to 5%). For N9-GP, precision of all parameters for all LSSs was acceptable (< 25%). For rFIXFc, precision was acceptable for CL and Time1%, except for t1/2 (range: 27.1% to 44.7%) and Dose1% (range: 12% to 29.4%). For rIX-FP, all LSSs showed acceptable bias and precision, except for Dose1% using LSS with the last sample taken on day 3 (LSS 6 and 10). Conclusion Best performing LSSs were LSS with samples taken at days 1, 5, 7, and 8 (N9-GP and rFIXFc) and at days 1, 4, 6, and 8 (rIX-FP), respectively.